Boric anhydrides of 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

ABSTRACT

The invention relates to new 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid/boric acid anhydrides of the general Formula I ##STR1## (wherein R and R 1  stand for halogen; an aliphatic acyloxy group comprising 2-6 carbon atoms and optionally substituted by halogen; or an aromatic acyloxy group comprising 7-11 carbon atoms). 
     The new compounds of the general Formula I are valuable intermediates useful in the preparation of the antibacterial agent 6-fluoro-1-methylamino-7-(4-methyl-piperazino)-4-oxo-1,4-dihydro-quinoline-3- carboxylic acid. 
     The new compounds of the general Formula I may be prepared by reacting a compound of the Formula II ##STR2## or a compound of the general Formula III ##STR3## (wherein R 2  stands for alkyl comprising 1-4 carbon atoms) with hydrogen fluoro borate of the Formula IV 
     
         HBF.sub.4                                                  /IV/ 
    
     or a borone trihalide of the general Formula V 
     
         BX.sub.3                                                   /V/ 
    
     (wherein X stands for fluorine, chlorine or bromine) or a complex thereof formed with an ether or a borone derivative of the general Formula VI ##STR4## (wherein R 3 , R 4  and R 5  stand for alkyl comprising 1-5 carbon atoms and optionally substituted by halogen or aryl comprising 6-10 carbon atoms).

This invention relates to new Amifloxacine intermediates and a processfor the preparation thereof. More particularly it is concerned with newanhydrides of6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylicacid and boric acids.

Ethyl-6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylateis an intermediate useful in the preparation of the antibacterial agent6-fluoro-1-methylamino-7-(4-methyl-piperazino)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (Journal of Medicinal Chemistry, 27, 1103, (1984). The lattercompound can be prepared in two steps fromethyl-6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylate.The said ester is subjected to hydrolysis whereupon the6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid thus obtained is reacted in the presence of a solvent at atemperature above 100° C. with 1-methyl-piperazine for 15-22 hours toyield the desired6-fluoro-1-methylamino-7-(4-methylpiperazino)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (European patent specification No. 90,424; Japanese patentspecification No. 84 01,468).

It has been found that the6-fluoro-1-methylamino-7-(4-methyl-piperazino)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid can be prepared under milder reaction conditions during a shorterreaction time by reacting 1-methyl-piperazine with a compound of theFormula I.

According to an aspect of the present invention there are provided newcompounds of the Formula I ##STR5## (wherein R and R¹ stand for halogen;an aliphatic acyloxy group comprising 2-6 carbon atoms and optionallysubstituted by halogen; or an aromatic acyloxy group comprising 7-11carbon atoms).

According to a further aspect of the present invention there is provideda process for the preparation of the compounds of the Formula I (whereinR and R¹ stand for halogen; an aliphatic acyloxy group comprising 2-6carbon atoms and optionally substituted by halogen; or an aromaticacyloxy group comprising 7-11 carbon atoms), which comprises

(a) reacting the quinoline-3-carboxylic acid derivative of the FormulaII ##STR6## with fluoroboric acid of the Formula IV or a trihalo borateof the Formula V

    BX.sub.3                                                   (V)

(wherein X stands for fluorine, chlorine or bromine) or a triacyloxyborate derivative of the Formula VI ##STR7## (wherein R³, R⁴ and R⁵stand for alkyl comprising 1-4 carbon atoms and optionally substitutedby halogen; or aryl comprising 6-10 carbon atoms); or

(b) reacting a quinoline derivative of the Formula III ##STR8## (whereinR² stands for hydrogen or alkyl comprising 1-4 carbon atoms) with fluoroboric acid of the Formula IV, or a trihalogeno borate of the Formula V(wherein X has the same meaning as stated above) or a triacyloxy borateof the Formula VI (wherein R³, R⁴ and R⁵ are as stated above).

As compound of the Formula V borone trifluoride, boron tribromide orboron trichloride or a complex or aqueous solution thereof can be used.One may preferably use a complex formed with an ether or alcohol (e.g. acomplex of boron trifluoride formed with tetrahydrofuran, diethyl ether,methanol, or propanol). One may preferably use a solution of a borontrihalide formed with an aliphatic hydrocarbon (e.g. dichloro methane)or a carboxylic acid (e.g. acetic acid, trifluoro acetic acid orpropionic acid).

The boric acid of the Formula IV, the boron trihalide of the Formula Vor the compound of the Formula VI can be used in a molar ratio of 1-50--preferably 1-5-- related to 1 mole of the compound of the Formula II orIII. The above molar ratio is however but a preferable feature and another molar ratio may be applied as well.

The above reactions may be carried out, if desired, in the presence of asolvent. As solvent e.g. water, ketones (e.g. acetone,methyl-ethyl-ketone), hydrocarbons (e.g. hexane, benzene, toluene),ethers (e.g. diethyl ether, dioxane, tetrahydrofuran), organic acids(e.g. acetic acid, propionic acid, trifluoro acetic acid, etc.) may beused.

The reactions can be carried out at room temperature, if desired.

On raising the reaction temperature, the reaction time can be shortened.Some reactions can be accomplished at a temperature between roomtemperature and 150° C. The reaction temperature depends on the solventused as well.

The compound of the Formula I thus obtained, precipitates from thereaction mixture spontaneously or on cooling and can be isolated byknown methods (e.g. filtration).

Further details of the present invention are to be found in thefollowing Examples without limiting the scope of protection to the saidExamples.

EXAMPLE 1

5 g ofethyl-6-fluoro-1-(N-formyl-N-methyl-amino)-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylateare stirred in 25 ml of an 50 weight/vol % aqueous solution of hydrogenfluoroboric acid at 90°-95° C. for 4 hours. After one hour and a halfthe precipitation of crystals begins. The reaction mixture is cooled toroom temperature, then placed into a refrigerator and allowed tocrystallize overnight. The precipitated crystals are filtered nextmorning and washed with some water. Thus 4.55 g of an anhydride of6-fluoro-7-chloro-1-(methylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid and difluoro boric acid are obtained, yield: 93.4%. Mp.: 277° C.(decomposition).

Analysis for the Formula C₁₁ H₇ BF₃ ClN₂ O₃ : calculated: C=41.48%,H=2.21%, N=8.79%; found: C=41.59%, H=2.34%, N=8.58%.

EXAMPLE 2

5 g of6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid are stirred in 25 ml of a 50 weight/vol % aqueous solution ofhydrogen fluoro boric acid at 80°-90° C. for 2 hours. After 45 minutesthe precipitation of crystals begins. The reaction mixture is firstcooled to room temperature and then allowed to crystallize for 2 hoursat 0° C. The precipitated crystals are filtered, and washed with somewater. Thus 4.95 g of an anhydride of6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid and difluoro boric acid are obtained, yield 84.5%. Mp.: 277° C.(decomposition). A mixture of the product thus obtained with any amountof the compound prepared according to Example 1 shows no melting pointdepression.

EXAMPLE 3

A mixture of 1.42 g of boric acid and 10.7 g of propionic anhydride isstirred at 100° C. for 15 minutes whereupon the reaction mixture isheated to boiling point. After 30 minutes the temperature of thereaction mixture is lowered to 110° C. and 4.2 g of6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid are added. After some minutes the precipitation of crystals begins.The reaction mixture is stirred at 110° C. for 2 hours, cooled to 10°C., whereupon 20 ml of water and 20 ml of ethanol are added to thecrystalline suspension. The reaction mixture is allowed to crystallizein a refrigerator overnight. The precipitated crystals are filtered,washed with water and dried. Thus 6.12 g of(6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid-boron-dipropionyloxy)-anhydride are obtained. Yield: 93.5%, Mp.:215° C. (decomposition).

Analysis for the Formula C₁₇ H₁₇ BFClN₂ O₇ : calculated: C=47.86%,H=4.01%, N=6.56%; found: C=48.07%, H=3.87%, N=6.48%.

EXAMPLE 4

0.568 g of boric acid and 3.28 g of acetic acid anhydride are reacted inthe presence of 1 mg zinc chloride, while the temperature of thereaction raises to 40° C. The white suspension is slowly heated to 100°C. and 2 g ethyl[7-chloro-6-fluoro-1,4-dihydro-1-(formylmethyl-amino)-4-oxo-3-quinoline-carboxylate]are added which had previously been dissolved in 10 ml of 96% by W/Vacetic acid. The reaction mixture is further heated at 110° C. for 2hours. The solution is cooled to room temperature and diluted with 40 mlof cold water. The precipitated crystals are filtered and washed withwater and cold abs. ethanol, and dried. Off-white crystalline[6-fluoro-7-chloro-1,4-dihydro-1-(methyl-amino)-4-oxo-3-quinolinecarboxylate-O³,O⁴]-bis(acetate-O)-boron is obtained (1.75 g).

Decomposition: 272° C.

Upon standing further 0.45 g product is precipitated from themother-liquor.

Analysis for the formula C₁₅ H₁₃ BClFN₂ O₇ : calculated: C=45.55%,H=3.31%, N=3.54%; found: C=45.2%, H=3.2%, N=3.6%.

What we claim is:
 1. A compound of the Formula I ##STR9## wherein R andR¹ stand for halogen; C₂ to C₆ alkanoyloxy or benzoyloxy.
 2. Thecompound of the Formula (I) defined in claim 1 wherein R and R¹ are eachbromine, chlorine or fluorine.
 3. The compound of the Formula (I)defined in claim 1 wherein R and R¹ are each acetoxy or propionyloxy. 4.A process for preparing a compound of the Formula (I) ##STR10## whereinR and R¹ are each bromine, chlorine or fluorine, which compriseshalogenating a compound of the Formula (II) ##STR11## or a compound ofthe Formula (III) ##STR12## wherein R² is C₁ to C₄ alkyl (a) withhydrogen fluoro borate of the formula (IV)

    HBF.sub.4

to yield the compound of the Formula (I) where R and R¹ are eachfluorine; or (b) with a boron trihalide of the Formula (V)

    BX.sub.3

where X is bromine, chlorine or fluorine, or a complex thereof formedwith an ether or an alcohol, to yield the compound of the Formula (I)where R and R¹ are each bromine, chlorine or fluorine.
 5. The processaccording to claim 4 which comprises carrying out the reaction of thecompound of the Formula II or III with the compound of the Formula IV inaqueous medium.
 6. The process according to claim 4 which comprisesreacting the compound of the Formula II or III with the compound of theFormula V in the presence of a solvent.